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61.
Gaál EI Salo P Kristiansson K Rehnström K Kettunen J Sarin AP Niemelä M Jula A Raitakari OT Lehtimäki T Eriksson JG Widen E Günel M Kurki M von und Zu Fraunberg M Jääskeläinen JE Hernesniemi J Järvelin MR Pouta A;International Consortium for Blood Pressure Genome-Wide Association Studies Newton-Cheh C Salomaa V Palotie A Perola M 《PLoS genetics》2012,8(3):e1002563
Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance. 相似文献
62.
Kyöstilä K Cizinauskas S Seppälä EH Suhonen E Jeserevics J Sukura A Syrjä P Lohi H 《PLoS genetics》2012,8(6):e1002759
Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (praw = 1.1×10−7, pgenome = 7.5×10−4). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD–mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders. 相似文献
63.
64.
Harkonmäki K Silventoinen K Levälahti E Pitkäniemi J Huunan-Seppälä A Klaukka T Koskenvuo M Kaprio J 《PloS one》2008,3(10):e3402
Background
No previous studies on the effect of genetic factors on the liability to disability retirement have been carried out. The main aim of this study was to investigate the contribution of genetic factors on disability retirement due to the most common medical causes, including depressive disorders.Methods
The study sample consisted of 24 043 participants (49.7% women) consisting of 11 186 complete same-sex twin pairs including 3519 monozygotic (MZ) and 7667dizygotic (DZ) pairs. Information on retirement events during 1.1.1975–31.12.2004, including disability pensions (DPs) with diagnoses, was obtained from the Finnish nationwide official pension registers. Correlations in liability for MZ and DZ twins and discrete time correlated frailty model were used to investigate the genetic liability to age at disability retirement.Results
The 30 year cumulative incidence of disability retirement was 20%. Under the best fitting genetic models, the heritability estimate for DPs due to any medical cause was 0.36 (95% CI 0.32–0.40), due to musculoskeletal disorders 0.37 (0.30–0.43), cardiovascular diseases 0.48 (0.39–0.57), mental disorders 0.42 (0.35–0.49) and all other reasons 0.24 (0.17–0.31). The effect of genetic factors decreased with increasing age of retirement. For DP due to depressive disorders, 28% of the variance was explained by environmental factors shared by family members (95% CI 21–36) and 58% of the variance by the age interval specific environmental factors (95% CI 44–71).Conclusions
A moderate genetic contribution to the variation of disability retirement due to any medical cause was found. The genetic effects appeared to be stronger at younger ages of disability retirement suggesting the increasing influence of environmental factors not shared with family members with increasing age. Familial aggregation in DPs due to depressive disorders was best explained by the common environmental factors and genetic factors were not needed to account for the pattern of familial aggregation. 相似文献65.
Hantaviruses are globally important human pathogens that cause hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Capillary leakage is central to hantaviral diseases, but how it develops, has remained unknown. It has been hypothesized that the pathogenesis of hantavirus infection would be a complex interplay between direct viral effects and immunopathological mechanisms. Both of these were studied in the so far best model of mild hemorrhagic fever with renal syndrome, i.e. cynomolgus macaques infected with wild-type Puumala hantavirus. Viral RNA detected by in situ hybridization and nucleocapsid protein detected by immunohistochemical staining were observed in kidney, spleen and liver tissues. Inflammatory cell infiltrations and tubular damage were found in the kidneys, and these infiltrations contained mainly CD8-type T-cells. Importantly, these results are consistent with those obtained from patients with hantaviral disease, thus showing that the macaque model of hantavirus infection mimics human infection also on the tissue level. Furthermore, both the markers of viral replication and the T-cells appeared to co-localize in the kidneys to the sites of tissue damage, suggesting that these two together might be responsible for the pathogenesis of hantavirus infection. 相似文献
66.
Leena Peltonen Piritta Koistinen Milja Karjalainen Antti Häkkinen Jouni Hirvonen 《AAPS PharmSciTech》2002,3(4):52-58
The aim of this study was to formulate nanoparticles from poly(I)lactide by a modified nanoprecipitation method. The main
focus was to study the effect of cosolvent selection on the shape, size, formation efficiency, degree of crystallinity, x-ray
diffraction (XRD) reflection pattern, and zeta potential value of the particles. Low-molecular-weight (2000 g/mol) poly(I)lactide
was used as a polymer, and sodium cromoglycate was used as a drug. Acetone, ethanol, and methanol were selected as cosolvents.
Optimal nanoparticles were achieved with ethanol as a cosolvent, and the formation efficiency of the particles was also higher
with ethanol as compared with acetone or methanol. The particles formulated by ethanol and acetone appeared round and smooth,
while with methanol they were slightly angular. When the volume of the inner phase was decreased during the nanoprecipitation
process, the mean particle size was also decreased with all the solvents, but the particles were more prone to aggregate.
The XRD reflection pattern and the degree of crystallinity were more dependent were more prone to aggregate. The XRD reflection
pattern and the degree of crystallinity were more dependent on the amount of the solvents in the inner phase than on the properties
of the individual cosolvents. The zeta potential values of all the particle batches were slightly negative, which partially
explains the increased tendency toward particle aggregation. 相似文献
67.
68.
Bactericidal effect of bovine normal and immune serum, colostrum and milk against Helicobacter pylori 总被引:4,自引:0,他引:4
H. Korhonen E.-L. Syväoja H. Ahola-Luttila S. Sivelä S. Kopola J. Husu T.U. Kosunen 《Journal of applied microbiology》1995,78(6):655-662
Serum and colostrum but not post-colostral milk from non-immunized Friesian cows was found highly bactericidal for Helicobacter pylori NCTC 11637. This bactericidal activity was destroyed by heating at 56°C for 30 min and restroed by the addition of fetal calf serum as a source of complement, indicating that the bactericidal effect was probably dependent on an antibody-complement system. Systemic, serial immunization of non-lactating, pregnant cows with H. pylori resulted in high specific antibody titres in serum and colostrum. No titres were found in post-colostral milk, even after booster-immunization during lactation. Immunization did not enhance the bactericidal activity of serum and colostrum, but increased it in post-colostral milk. The bactericidal activity was not correlated with titres of specific antibody or with IgG concentrations. 相似文献
69.
Reviews in Fish Biology and Fisheries - 相似文献
70.
Ornithine Decarboxylase Activity in Brain Regulated by a Specific Macromolecul, the Antizyme 总被引:1,自引:0,他引:1
Paivi H. Laitinen Riitta-Liisa Huhtinen Oili A. Hietala Antti E. I. Pajunen 《Journal of neurochemistry》1985,44(6):1885-1891
Mouse brain ornithine decarboxylase activity is about 70-fold higher at the time of birth compared with that of adult mice. Enzyme activity declines rapidly after birth and reaches the adult level by 3 weeks. Immunoreactive enzyme concentration parallels very closely the decrease of enzyme activity during the first postnatal week, remaining constant thereafter. The content of brain antizyme, the macromolecular inhibitor to ornithine decarboxylase, in turn is very low during the first 7 days and starts then to increase and at the age of 3 weeks it is about six times the level of that in newborn mice. This may explain the decrease in enzyme activity during brain maturation, and suggests the regulation of polyamine biosynthesis by an antizyme-mediated mechanism in adult brain. 相似文献